Short Chain Fatty Acids (SCFAs) and SCFA G-protein Coupled Receptors in Hypertension

Information

  • Research Project
  • 10476066
  • ApplicationId
    10476066
  • Core Project Number
    R56DK107726
  • Full Project Number
    2R56DK107726-06A1
  • Serial Number
    107726
  • FOA Number
    PA-20-185
  • Sub Project Id
  • Project Start Date
    12/1/2015 - 8 years ago
  • Project End Date
    7/31/2022 - a year ago
  • Program Officer Name
    MARIC-BILKAN, CHRISTINE
  • Budget Start Date
    9/15/2021 - 2 years ago
  • Budget End Date
    7/31/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    06
  • Suffix
    A1
  • Award Notice Date
    9/15/2021 - 2 years ago
Organizations

Short Chain Fatty Acids (SCFAs) and SCFA G-protein Coupled Receptors in Hypertension

Project Summary Metabolites produced by the gut microbiota play critical roles in host physiology and pathophysiology. We have previously shown that one class of microbial metabolites, short chain fatty acids (SCFAs), bind to host G protein-coupled receptors (GPCRs) to modulate blood pressure. We have found that SCFAs activate Olfactory Receptor 78 (Olfr78) to modulate renin release, and activate Gpr41 to modulate vascular tone. Recently, we have identified two other GPCRs (Gpr43 and Olfr558) which respond to SCFAs and are expressed in the vasculature, and thus are well-positioned to also influence blood pressure. In this proposal, we Aim to investigate how SCFA-GPCR signaling pathways modulate ? and are modulated by ? hypertension. In Specific Aim 1, we will examine how components of the SCFA signaling pathway (SCFAs, as well as SCFA GPCRs) are modulated in two different models of hypertension (Angiotensin II, and DOCA/Salt). Plasma SCFAs increase in hypertension; here, we will test our novel hypothesis that altered host handling of SCFAs, not increased microbial production, is key in determining plasma levels. To achieve this, we will measure microbial production, intestinal reabsorption, and renal clearance of SCFAs in normotension and in two hypertension models. To examine SCFA GPCRs in hypertension, we will determine how the expression of Olfr78, Olfr558, Gpr41, and Gpr43 is altered in normotension versus hypertension. In Specific Aim 2 of this proposal, we will determine how each of these components of the SCFA-GPCR signaling pathway can modulate the course of hypertension. We have extensively studied Olfr78 and Gpr41 in the past, therefore, we will focus on uncovering novel roles for Olfr558 and Gpr43 in blood pressure regulation under basal conditions and in hypertension. In a separate experiment, we will test our novel hypothesis that low doses of SCFAs are protective but higher doses of SCFAs are detrimental, thereby resolving a conflict in the literature. To do this, we will treat normotensive and hypertensive mice with varying doses of exogenous SCFAs. In sum, these studies will advance the field by illuminating how SCFAs and SCFA GPCRs are modulated in hypertension, and by determining how modulation of this pathway can alter the course of hypertension.

IC Name
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
  • Activity
    R56
  • Administering IC
    DK
  • Application Type
    2
  • Direct Cost Amount
    61069
  • Indirect Cost Amount
    38931
  • Total Cost
    100000
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    847
  • Ed Inst. Type
    SCHOOLS OF MEDICINE
  • Funding ICs
    NIDDK:100000\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    IVPP
  • Study Section Name
    Integrative Vascular Physiology and Pathology Study Section
  • Organization Name
    JOHNS HOPKINS UNIVERSITY
  • Organization Department
    PHYSIOLOGY
  • Organization DUNS
    001910777
  • Organization City
    BALTIMORE
  • Organization State
    MD
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    212182680
  • Organization District
    UNITED STATES